Several naturally-occurring alkaloids obtainable from Vinca rosea have been found active in the treatment of experimental malignancies in animals. Among these are leurosine (U.S. Pat. No. 3,370,057), vincaleukoblastine (vinblastine) to be referred to hereinafter as VLB (U.S. Pat. No. 3,097,137), leurosidine (vinrosidine) and leurocristine (VCR or vincristine) (both in U.S. Pat. No. 3,205,220). Two of these alkaloids, VLB and vincristine are now marketed as drugs for the treatment of malignancies, particularly the leukemias and related diseases in humans. Of these marketed compounds, vincristine is a most active and useful agent in the treatment of leukemias but is also the least abundant of the anti-neoplastic alkaloids of Vinca rosea. It is most desirable to increase the supply of vincristine, either by recovering more of the compound in the extraction process from Vinca leaves (see South African Pat. No. 72/8534), or by converting more abundant dimeric Vinca alkaloids, such as VLB, by chemical or biological methods to vincristine (see South African Pat. No. 72/8534). In addition, there is also the possibility of converting a less active alkaloid to VLB which can in turn be oxidized to vincristine.
The three most active naturally-occurring, antineoplastic alkaloids from Vinca rosea, VLB, vincristine and leurosidine, can be represented by the following formula: ##STR1## In VLB, R is methoxy, R' is acetoxy, R" is methyl, R'" is hydroxyl and R"" is ethyl. In leurosidine, R, R' and R" are the same as in VLB but the configuration at C-4' is reversed; i.e., R'" is ethyl and R"" is hydroxyl. In vincristine, R, R', R'" and R"" are the same as in VLB but R" is formyl. Another dimeric indole alkaloid useful as an intermediate is des-N-methyl VLB (also known as des-N-formylvincristine) with the same substituents as either VLB or vincristine except that R" is H. Des-N-methyl VLB is conveniently prepared by deformylation of vincristine.
Chemical modification of the Vinca alkaloids has been rather limited. In the first place, the molecular structures involved are extremely complex and chemical reactions which affect a specific function of the molecule are difficult to develop. Secondly, alkaloids lacking desirable chemotherapeutic properties have been recovered from Vinca rosea fractions, and a determination of their structures has led to the conclusion that these compounds are closely related to the active alkaloids. Thus, anti-neoplastic activity seems to be limited to very specific structures, and the chances of obtaining more active drugs by modification of these structures would seem to be correspondingly slight. Among the successful modifications of physiologically-active alkaloids has been hydrogenation of the .DELTA..sup.6 double bond-- dihydro VLB (U.S. Pat. No. 3,352,868 )-- and the replacement of the acetyl group at C-4 (carbon no. 4 of the VLB ring system-- see the numbered structure below) with a higher alkanoyl group or with unrelated acyl groups (see U.S. Pat. No. 3,392,173). Several of these derivatives are capable of prolonging the life of mice inoculated with P1534 leukemia. One of the derivatives in which a chloracetyl group replaced the C-4 acetyl group of VLB was also a useful intermediate for the preparation of structurally modified VLB compounds in which an N,N-dialkylglycyl group replaced the C-4 acetyl group of VLB (see U.S. Pat. No. 3,387,001).
Another recent modification of the indole-dihydro indole alkaloid structure has been the preparation of C-3 carboxamides and hydrazides of VLB, vincristine, leurosidine and their C-4 desacetyl derivatives (see Belgian Pat. No. 813,168, granted Oct. 2, 1974).
Atta-ur-Rahman, Pakistan J. Sci. Ind. Res., 14, 487 (1971) stated that he had prepared 3',4'-anhydro VLB by the condensation of carbomethoxy chlorocleavamine and vindoline. However, Kutney et al., Heterocycles, 3, 205 (1975) have demonstrated conclusively that the condensation product was, in fact, 18'-epi-3',4'-dehydro VLB, possessing the non-natural VLB stereochemistry at C-18'. Authentic 3',4'-anhydro VLB derivatives possessing the "natural" configuration at C-18' are not described elsewhere in the art.
It is an object of this invention to provide a series of new dimeric indole-dihydroindole alkaloids showing activity against experimental tumors in mice such as Ridgeway osteogenic Sarcoma and Gardner lymphosarcoma or as intermediates for the preparation of other anti-neoplastically active compounds.